Abstract
Objective
To investigate the relation of circulating 25‐hydroxyvitamin D (25[OH]D) levels to age, sex, and bone mineral density (BMD) in adults living in Guangzhou Province.
Methods
This cross‐sectional study comprised 188 women and 122 men aged 17–88 years who were randomly sampled among community‐dwelling Guangzhou residents. BMD at the lumbar spine and femoral neck was measured by dual energy X‐ray absorptiometry, and serum concentrations of 25(OH)D, parathyroid hormone (PTH), procollagen I N‐terminal peptide, and beta C‐telopeptide of collagen were assayed by electrochemiluminescence immunoassay. Serum 25(OH)D concentrations were divided into four subgroups: severe deficiency (<10 ng/mL), deficiency (10–20 ng/mL), insufficiency (20–30 ng/mL), and sufficiency (≥30 ng/mL).
Results
The mean age of participants was 47.39 ± 19.32 years. Serum 25(OH)D levels were significantly lower in women than men (25.35 ± 6.59 ng/mL vs 27.25 ± 7.94 ng/mL, P < 0.05). The prevalence of 25(OH)D severe deficiency (<10 ng/mL) was 1.6% in men, zero in women; 25(OH)D deficiency (10–20 ng/mL) was 22.9% in women and 20.5% in men; and 25(OH)D insufficiency (20–30 ng/mL) was 73.4% in women and 65.6% in men. An inverse relationship between serum 25(OH)D levels and age (r = −0.249, P < 0.01) was observed in men, but no correlation was found in women (r = 0.130, P > 0.05). Serum 25(OH)D levels were positively associated with lumbar spine and femoral neck BMD (r = 0.382, P < 0.01; r = 0.384, P < 0.01, respectively) in elderly women and (r = 0.332, P < 0.05; r = 0.260, P < 0.05, respectively) and in young men. When adjustments were made for age, correlations between serum 25(OH)D levels and lumbar spine and femoral neck BMD persisted (r = 0.325, P < 0.05; r = 0.323, P < 0.05, respectively) in elderly women. However, age‐adjusted serum 25(OH)D levels were positively correlated with BMD at lumbar spine (r = 0.278, P < 0.05) but not at femoral neck (r = 0.165, P > 0.05) in young men. No association between unadjusted or age‐adjusted serum 25(OH)D levels and lumbar spine and femoral neck BMD was found in young and middle‐aged women and in middle‐aged and elderly men. Neither serum PTH levels nor bone turnover markers were related to unadjusted and age‐adjusted serum 25(OH)D levels in our participants.
Conclusion
More than two‐third of participants residing in Guangzhou had vitamin D insufficiency. Serum 25(OH)D level is an important biomarker for BMD in elderly women and young men.
Keywords: 25 hydroxyvitamin D, Age, Bone mineral density, Bone turnover markers
Introduction
Vitamin D is considered essential for bone health in children and adults1. Recent studies have shown that vitamin D insufficiency is correlated with bone mineral density (BMD) and osteoporosis2, 3. In addition, there has been increasing interest in the influence of vitamin D insufficiency on non‐skeletal diseases, including cardiovascular disease4, diabetes5, 6, secondary hyperparathyroidism7, multiple sclerosis8, cancers9, infection10, rheumatology11, and hyperuricemia12.
The level of circulating 25‐hydroxyvitamin D (25[OH]D) is a biomarker of the vitamin D status of a human being. Unfortunately, the cut‐off levels of serum 25(OH)D that represent vitamin D insufficiency have not yet been clearly defined13. At present, a circulating level of 25(OH)D of less than 20 ng/mL it is frequently used as a measure of deficiency, whereas a circulating level of 25(OH)D of less than 30 ng/mL is used as a measure of insufficiency in China1, 14. Recently, Lu et al. showed that Shanghai adults exhibited a high prevalence of vitamin D insufficiency (25(OH)D < 30 ng/mL), in about 84% of men and 89% of women. In addition, the levels of procollagen 1 N‐terminal peptide (PINP) and beta C‐telopeptide of collagen (β‐CTX) started to increase when serum 25(OH)D levels were lower than 30 ng/mL15. Wat et al. reported that 62.8% of Hong Kong adults had 25(OH)D levels below 30 ng/mL. Additionally, parathyroid hormone (PTH) began to rise when 25(OH)D levels were below 30 ng/mL, whereas PTH levels did not change when 25(OH)D levels were above 30 ng/mL16. Zhu et al. demonstrated that 89.6% of Hangzhou adolescents had 25(OH)D levels of less than 30 ng/mL17. In India, a tropical Asian country, only 6% of Indian health‐care professionals had levels were above 30 ng/mL18. As we known, sun exposure is the most important source of vitamin D for most humans19. However, available evidence from studies in Shanghai, Hong Kong, Hangzhou, and India indicate that participants had abundant exposure to sunlight but vitamin D insufficiency was widespread.
Based on the above studies in humans, we speculate that Vitamin D insufficiency is very common in southern Chinese children and adults, but there are few reports on its prevalence in Guangzhou residents. Therefore, the aims of this study were to: (i) investigate the prevalence of vitamin D insufficiency in Guangzhou and (ii) evaluate the relation of circulating 25(OH)D levels to age, sex, and BMD in Guangzhou adults.
Materials and Methods
Study Design
This was a cross‐sectional study of women and men in China. A total of 380 healthy subjects with ages ranging from 17 to 88 years, consisting of 215 women and 165 men who were randomly selected from May 2012 to August 2012 were included. We included participants who were recruited from population registers and confirmed they had been living in Guangzhou for at least 5 years. All were asked to visit an outpatient clinic at the departments of osteoporosis and rehabilitation, General Hospital of Guangzhou Military Command of the People's Liberation Army (PLA). Their anthropometrics, life style, smoking and alcohol habits, disease history, and use of medications were recorded. All participants underwent fasting plasma glucose, liver and kidney function tests. No participant was included who had known diseases that affect bone metabolism, including diabetes mellitus, hyperparathyroidism, thyroid disorders, liver and kidney diseases, cancer, rheumatoid arthritis, or other metabolic diseases. In addition, participants who had taken Vitamine D, calcium supplements or corticosteroids within the previous 12 months were also excluded. For the present analysis, we excluded 27 women and 43 men who were had diseases and were taking medications that could potentially affect their circulating 25(OH)D levels.
The study was approved by the Ethical Committee of the General Hospital of Guangzhou Military Command of the PLA, and all subjects signed written, informed consent forms prior to the evaluation.
Serum Analysis
All blood samples were taken from the antecubital vein of each participant in the morning after an overnight fast. The blood was centrifuged for 10 minutes at 1000 g after clotting for 2 h at room temperature to obtain serum. The serum was divided into 0.5 mL aliquots, placed in Eppendorf tubes and stored at −80 °C until they were used for different assays. The samples were thawed slowly at room temperature before use. The levels of serum 25(OH)D, PTH, PINP, and β‐CTX were measured by electrochemiluminescence immunoassay (Cobase 411, Roche Diagnostics, Mannheim, Germany). All samples were analyzed using the same kit (Roche). The intra‐assay coefficients of variation (CVs) for 25(OH)D were 7.5% at a level of 7.16 ng/mL, 5.0% at a level of 15.6 ng/mL, 3.0% at a level of 28.7 ng/mL, and 1.7% at a level of 67.9 ng/mL. The inter‐assay CVs for 25(OH)D were 13.6% at a level of 7.16 ng/ml, 8.8% at a level of 15.6 ng/ml, 5.5% at a level of 28.7 ng/mL, and 2.2% at a level of 67.9 ng/mL. The lower limit of detection of 25(OH)D was <3 ng/mL (<7.5 nmol/L), and the higher limit of detection of 25(OH)D was >70 ng/mL (>175 nmol/L). The intra‐assay and inter‐assay CVs for PTH were 4.5% and 6.4%, respectively, for PINP, 6.5% and 6.1%, respectively, for β‐CTX, 4.3% and 5.8%, respectively.
Bone Mineral Density Examination
In all subjects, BMD was determined by Dual Energy X‐ray Absorptiometry (DEXA; Lunar Prodigy, GE Medical Systems, Madison, WI, USA). From this, we were able to obtain BMD of the spine regions including lumbar vertebrae 1–4 and the femoral neck area. To eliminate operator differences, the same operator tested all participants in the study. Duplicate measurements were obtained from 30 participants who underwent a repeat assessment on the same day, and the precision errors were calculated using the root mean square method. The CVs precision measurements of the lumbar spine and femoral neck were 0.60% and 0.89%, respectively.
Statistical Analysis
The results were presented as mean ± standard deviation (SD). A one‐way anova and Dunnett's post hoc test was performed to compare the results of multiple groups. For experiments involving two groups, a two‐sample t test was performed. Unadjusted and age‐adjusted Pearson's correlation analysis was calculated to evaluate the associations between serum 25(OH)D levels and other measured variables. Locally weighted regression and Loes ssmoothing scatterplots were used to study the relationship of serum 25(OH)D with age in both sexes. Serum 25(OH)D and BMD at the lumbar spine and femoral neck were also plotted against each other to discern their mutual relationship in both sexes. A P value of less than 0.05 was considered statistically significant. All analyses were performed using SPSS vers. 18.0 (IBM, Armonk, NY, USA) software.
Results
Based on the exclusion criteria, 27 women and 43 men were excluded from this study and the results of the remaining 310 subjects were included for analysis. The age categories, biochemical testing variables and BMD data of the 188 women and 122 men aged 17–88 years are shown in Table 1. All participants were of Han ethnicity and were residents of Guangzhou Province.
Table 1.
Participants' characteristics
| Items | Total sample (n = 310) | Women (n = 188) | Men (n = 122) | Statistical value |
|---|---|---|---|---|
| Age (mean ± SD, years) | 47.39 ± 19.32 | 49.67 ± 17.61 | 43.89 ± 21.29* | −2.498 |
| 17–39 (n, %) | 121 (39.0) | 63 (33.5) | 58 (47.5) | |
| 40–59 (n, %) | 99 (31.9) | 69 (36.7) | 30 (24.6) | |
| ≥60 (n, %) | 90 (29.0) | 56 (29.8) | 34 (27.9) | |
| Serum 25(OH)D (mean ± SD, ng/mL) | 26.10 ± 7.20 | 25.35 ± 6.59 | 27.25 ± 7.94* | 2.190 |
| <10 (n, %) | 2 (0.6) | 0 (0) | 2 (1.6) | |
| 10–20 (n, %) | 66 (21.3) | 43 (22.9) | 23 (18.9) | |
| 20–30 (n, %) | 150 (48.4) | 95 (50.5) | 55 (45.1) | |
| ≥30 (n, %) | 92 (29.7) | 50 (26.6) | 42 (34.4) | |
| Serum PTH (mean ± SD, pg/mL) | 15.42 ± 11.11 | 16.22 ± 11.91 | 14.17 ± 9.68 | −1.659 |
| Serum PINP (mean ± SD, μg/L) | 56.95 ± 33.20 | 49.22 ± 25.52 | 68.88 ± 39.65*** | 4.862 |
| Serum β‐CTX (mean ± SD, μg/L) | 0.42 ± 0.26 | 0.40 ± 0.25 | 0.45 ± 0.26 | 1.687 |
| Lumbar spine BMD (mean ± SD, g/cm2) | 1.09 ± 0.18 | 1.04 ± 0.17 | 1.17 ± 0.18*** | 6.220 |
| Femoral neck BMD (mean ± SD, g/cm2) | 0.89 ± 0.17 | 0.84 ± 0.15 | 0.97 ± 0.18*** | 6.758 |
Note: *P < 0.05; **P < 0.01; ***P < 0.001 versus women group. P value by two‐sample t‐test (versus women). 25‐hydroxyvitamin (25(OH)D), BMD, bone mineral density; PINP, procollagen I N‐terminal peptide; PTH, parathyroid hormone; β‐CTX, beta C‐telopeptide of collagen.
The mean serum concentrations of 25(OH)D, PTH, PINP and β‐CTX were 26.10 ± 7.20 (range, 8.15–49.69) ng/mL, 15.42 ± 11.11 (range, 0.50–58.00) pg/mL, 56.95 ± 33.20 (range, 10.05–192.50) μg/L, and 0.42 ± 0.26 (range, 0.06–2.51) μg/L, respectively. In addition, the mean BMD data of the lumbar spine and femoral neck were 1.09 ± 0.18 (range, 0.54–1.76) g/cm2 and 0.89 ± 0.17 (range, 0.46–1.45) g/cm2, respectively. On average, men had significantly higher 25(OH)D and PINP concentrations than women (P < 0.05). However, PTH levels were higher and β‐CTX levels were lower in women than in men, although the P value was greater than 0.05. Moreover, BMD values at both sites were higher in men than in women (P < 0.001 for both).
Serum 25(OH)D concentrations were divided into four subgroups: severe deficiency (<10 ng/mL), deficiency (10–20 ng/mL), insufficiency (20–30 ng/mL), and sufficiency (≥30 ng/mL). The prevalence of severe vitamin D deficiency was 1.6% in men, but was not observed in women. In total 43 (22.9%) women and 25 (20.5%) men had 25(OH)D levels below 20 ng/mL. Moreover, 138 (73.4%) women and 80 (65.6%) men had 25(OH)D levels below 30 ng/mL.
The association between 25(OH)D levels and age was analyzed. There was no correlation between the levels of 25(OH)D and age (r = 0.130, P = 0.075) in women (Fig. 1). Interestingly, in women a relatively stationary phase was observed in those younger than 40‐years old, a relatively steep increase was observed in those aged between 40 and 59 years, and a relatively steep decrease was observed in those after 60 years of age. Figure 2 shows the inverse association between the 25(OH)D levels with age (r = −0.249, P = 0.006). A Loess plot exhibited a relatively steep decrease in men younger than 40 years old, a relatively stationary phase men aged between 40 and 59 years, and a relatively slow decrease after men were older than 60 years. In order to reduce confounding by age, we divided the participants into three groups: young (17–39 years), middle‐aged (40–59 years) and elderly (≥60 years). Interestingly, there was no association between 25(OH)D levels and age in middle‐aged (r = 0.074, P = 0.544) and elderly women (r = −0.234, P = 0.082), but a weakly inverse correlation between 25(OH)D and age in young men (r = −0.259, P = 0.049). In addition, serum 25(OH)D levels were significantly higher in middle‐aged (26.54 ± 6.36, P < 0.001) and elderly women (26.11 ± 8.19, P < 0.05) than in young women (23.39 ± 4.59). As for men, the levels of 25(OH)D in middle‐aged men (24.60 ± 7.96; by anova, P < 0.05) were inferior to young (29.15 ± 7.56) and elderly men (26.35 ± 7.95).
Figure 1.
Relationship between serum 25‐hydroxyvitamin D (25[OH]D) levels and age in women (188 cases). Correlation coefficients are as noted. Loess plots show the trends in 25(OH)D levels changing with age.
Figure 2.
Relationship between serum 25‐hydroxyvitamin D (25[OH]D) levels and age in men (122 cases). Correlation coefficients are as noted. Loess plots show the trends in 25(OH)D levels changing with age.
Table 2 shows the relation between serum 25(OH)D levels and BMD at different sites in three age groups of women and men. In the elderly women, unadjusted and age‐adjusted BMD at the lumbar spine and femoral neck were positively associated with 25(OH)D levels. By contrast, BMD at the lumbar spine was positively correlated with 25(OH)D levels in the young men. There was no association between 25(OH)D levels and BMD at both sites in young and middle‐aged women or middle‐aged and elderly men.
Table 2.
Correlation analysis between serum 25‐hydroxyvitamin D (25(OH)D) levels and bone mineral density in women and men (coefficients: unadjusted/age‐adjusted)
| BMD | Women (age, years) | Men (age, years) | ||||
|---|---|---|---|---|---|---|
| 17–39 | 40–59 | ≥60 | 17–39 | 40–59 | ≥60 | |
| LS | 0.118/0.140 | 0.141/0.180 | 0.382*/0.325* | 0.332*/0.278* | 0.147/0.131 | 0.188/0.167 |
| FN | 0.203/0.186 | 0.187/0.204 | 0.384*/0.323* | 0.260*/0.165 | −0.001/0.041 | 0.148/0.043 |
Note: Data expressed are Pearson correlation coefficients (r). BMD, bone mineral density; FN, femoral neck; LS, lumbar spine.
*P < 0.05.
Table 3 shows the unadjusted and age‐adjusted serum 25(OH)D levels versus biochemical parameters in women and men in three age groups. Interestingly, none of these biochemical parameters were related to the age‐adjusted 25(OH)D levels in the three age groups of women and men.
Table 3.
Correlation analysis between serum 25‐hydroxyvitamin D (25(OH)D) levels and bone biochemical markers in women and men (coefficients: unadjusted/age‐adjusted)
| Biochemical markers | Women (age, years) | Men (age, years) | ||||
|---|---|---|---|---|---|---|
| 17–39 | 40–59 | ≥60 | 17–39 | 40–59 | ≥60 | |
| PTH | 0.013/0.003 | −0.194/−0.186 | −0.117/−0.157 | −0.010/−0.058 | −0.242/−0.241 | 0.359*/0.338 |
| PINP | −0.040/−0.099 | −0.180/−0.185 | −0.203/−0.186 | 0.153/0.004 | −0.088/−0.078 | −0.145/−0.170 |
| β‐CTX | −0.161/−0.241 | −0.126/−0.156 | −0.126/−0.107 | −0.246/−0.255 | −0.204/−0.194 | −0.257/−0.258 |
Note: *P < 0.05. Data expressed are Pearson correlation coefficients (r). β‐CTX, beta C‐telopeptide of collagen; PINP, procollagen I N‐terminal peptide; PTH, parathyroid hormone.
Discussion
Guangzhou is located in southern China, adjacent to Hong Kong and with a subtropical latitude of 23.1°N, where high sunlight is available to provide ample light all year round. Guangzhou residents were expected to have a lower prevalence of vitamin D insufficiency compared with people living at high latitudes. However, the present results suggested that vitamin D insufficiency was commonly found in healthy women and men living in Guangzhou. Guangzhou is a flourishing international commercial city with a population of over 12 million and where the numbers of vehicles have reached 1.7 million. The main reason for vitamin D insufficiency may be attributed to people's lifestyle changes, undertaking fewer outdoor activities. Moreover, air pollution‐related haze from vehicular sources decreases exposure to sunlight, thereby reducing UVB‐induced vitamin D synthesis in the skin19, 20. In addition, very few foods naturally contain vitamin D. Lv et al. showed that Chinese‐American women had a high risk of osteoporosis due to their inadequate calcium and vitamin D intake from normal dietary sources21. Taking together with previous studies in Caucasians22, 23, Africans24, and Asians15, 16, 17, 18, 25, we verify the observation that vitamin D insufficiency is prevalent among populations around the world, and regions with sunny climates are no exception.
Circulating 25(OH)D concentration is the best clinical indicator of vitamin D status in the blood. Omdahl et al. showed that serum 25(OH)D levels were lower in the elderly than in a young population, and higher in men than in women26. Our data demonstrate that serum 25(OH)D levels were significantly lower in young women than middle‐aged and elderly women. As for the men, the levels of 25(OH)D in middle‐aged men were lower than in young and elderly men. In the elderly population, no significant difference was found between women and men (P = 0.892). At present, there is no consistent conclusions can be made for the association of serum 25(OH)D concentrations with age. Some studies have found an inverse association between 25(OH)D levels and age in elderly women or men (>65 years)27, 28, 29, but other have not30. We found that there was an inverse correlation between 25(OH)D levels and age in men. It was worth noting that the 25(OH)D level starts to decline in people from 17 years of age and had a stationary phase in people after 40 years old. Although there was no association between the levels of 25(OH)D and age in women, we found that 25(OH)D level began to decrease significantly after they were 60 years old, this result was similar to previous studies28, 29. Thus, we could not exclude the possibility that the age‐related confounding factors influence circulating 25(OH)D concentrations.
Vitamin D status is an important determinant of bone health. However, there is controversy regarding the association between 25(OH)D levels and BMD. Some studies have reported a positive association between serum 25(OH)D levels and BMD at the hip and spine31, 32, 33, 34; while others have found no association16, 35, 36. To reduce the potential confounding age‐related factors, we divided our cohort into young, middle‐aged and elderly groups. We found that BMD at the lumbar spine and femoral neck were positively associated with 25(OH)D levels in elderly women after adjustment for age, and age‐adjusted BMD at the lumbar spine was positively correlated with 25(OH)D levels in young men. BMD at the lumbar spine and femoral neck were not correlated with 25(OH)D levels in young and middle‐aged women or middle‐aged or elderly men. This result was consistent with the work of Lim et al., who have shown that there was a positive correlation between serum 25(OH)D and BMD in men aged 23 to 40 years, but no such correlation was observed in women37. However, Shivane et al., who reported a positive association between serum 25(OH)D and BMD at the hip in men aged 25 to 30 years38, while our study associated BMD at the lumbar spine with young men. Moreover, von Mühlen et al. showed that age‐adjusted 25(OH)D levels were related to BMD at the hip in postmenopausal women (aged 50–97 years)33. Bhattoa et al. showed that 25(OH)D levels were significantly associated with BMD at the femoral neck in postmenopausal women39. But Garnero et al. indicated that 25(OH)D levels were not related to BMD at the hip in postmenopausal women (mean age 62.2 years)36. Little is understood about vitamin D status in relation to BMD at the lumbar spine and femoral neck in elderly women (>60‐years old). According to our results, we strongly recommended taking vitamin D supplements when the circulating 25(OH)D level is below 30 ng/mL, especially, in elderly women and young men because maintaining circulating levels of 25(OH)D above 30 ng/mL is beneficial to bone health.
Optimal vitamin D levels inhibit the secretion of PTH, which is necessary to prevent secondary hyperparathyroidism and bone loss33. However, there is a debate regarding the relationship between 25(OH)D levels and PTH. Our results found that there was no significant association between age‐adjusted 25(OH)D and PTH levels in three age groups of both sexes. This result is in agreement with some previous studies31, 33, but not in all15, 32. Likewise, there is also a controversy on the relationship between 25(OH)D levels and bone turnover markers. Allali et al. showed that patients with hypovitaminosis D had a high bone turnover, whereas it had no effect on BMD35. The current study is in line with precious studies36. We found that age‐adjusted 25(OH)D did not correlate with bone turnover markers in the three age groups of both sexes. This suggests that it is inappropriate to use increased serum PTH and bone turnover levels as a surrogate indicator for vitamin D deficiency or insufficiency in the subjects under investigation.
The superiority of this study includes its large sample size and very strict, detailed inclusion criteria. This research was a population‐based study, and participants were sampled from several community‐dwelling residents in Guangzhou. Therefore, selection bias may arise because healthy adults are more likely to participate in the study. The main limitation of the current study was its cross‐sectional design, hence, insufficient causality could be demonstrated for the relationship between serum 25(OH)D and other variables.
In conclusion, our results indicated that vitamin D insufficiency is very common (73.4% of women and 65.6% of men with vitamin D levels below 30 ng/mL) in healthy adults living in Guangzhou. A relatively steep decrease in the 25(OH)D level was found in elderly women, and the same tendency was observed in young men. In age‐adjusted analyses serum 25(OH)D levels were positively related to BMD at the lumbar spine and femoral neck in elderly women and positively associated with BMD at the lumbar spine in young men, whereas serum 25(OH)D levels whad no effect on PTH and bone turnover status in both sexes. Further studies are needed to elucidate the clinical impact of the above findings.
Acknowledgments
Qiu‐shi Wei and Zhen‐qiu Chen contributed equally to this study as co‐first author. This research was supported by grants from the project of the National Natural Science Foundation of China (81302994 81273778) and the National Natural Science Foundation of Guangdong Province (S2013040014927). We thank all the colleagues for their invaluable assistance during the execution of the present study.
Disclosure: The authors declare that they have no conflict of interest.
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